Anticancer agents have various types such as an alkylating agent, a platinum agent, an antimetabolite, an anticancer antibiotic, and an anticancer plant alkaloid. These anticancer agents are effective for some cancers but not effective for other cancers. Even when an anticancer agent is confirmed to be effective for a certain cancer, the anticancer agent is effective for some patients and not effective for other patients. The parameter showing whether or not the anticancer agent exhibits the effect on the cancer of a specific patient is called sensitivity to the anticancer agent.
Irinotecan hydrochloride (CPT-11) is an anticancer agent which has been developed in Japan and which has an action mechanism based on the inhibition of topoisomerase I. In Japan, CPT-11 indicated for non-small-cell lung cancer, small-cell lung cancer, cervical cancer, and ovarian cancer was approved as an effective drug in January 1994. Further, CPT-11 indicated for gastric cancer, colorectal cancer, breast cancer, squamous cell carcinoma, and malignant lymphoma was approved in July 1995. CPT-11 in multi-drug therapy has been recognized to be one of standard chemotherapy, in particular, as a first line drug or a second line drug for colorectal cancer all over the world, and the efficacy of CPT-11 has been established.
Meanwhile, clinical performance including survival rate attained by chemotherapy of advanced or metastatic colorectal cancer has been drastically improved through a combination therapy employing a key drug such as CPT-11 or oxaliplatin, which was developed in 1990s, and a fluoro-pyrimidine drug such as fluorouracil (5-FU), which had been a main drug for the therapy of colorectal cancer. However, the response rate of such chemotherapy is as low as about 50%. That is, the chemotherapy is not effective for half of the patients to whom an anticancer agent has been administered with high risks such as serious adverse events. Thus, there is urgent demand for establishing a method for predicting the sensitivity of a patient to an anticancer agent, which method enables determination of therapeutic response of individual patients (i.e., indication of a responder or non-responder).
Generally, the therapy schedule of cancer chemotherapy requires a long period of time. After repetition of several courses of chemotherapy while emergence of adverse events is monitored, attainment of a therapeutic effect and continuation of the therapy are assessed. The assessment requires a long period of time and high medical cost, and the adverse events have actually been observed to a certain degree. Thus, if there were means for predicting whether or not individual patients can receive the effect of chemotherapy before or in an early stage of the therapy, the burden of the patients and emergence of adverse events can be reduced or mitigated, leading to reduction in medical cost.
Although CPT-11 itself has antitumor activity, CPT-11 is activated by carboxyl esterase in the body, to thereby form 7-ethyl-10-hydroxycamptothecin (SN-38), which has 100 to several thousand times stronger antitumor activity compared to that of CPT-11. Co-presence of CPT-11 and SN-38 in the body is thought to provide an antitumor effect. In hepatocytes, SN-38 is glucuronidated by UDP-glucuronosyltransferase (UGT), to thereby form SN-38 glucuronate conjugate (SN-38G) having no cytotoxicity. SN-38G is excreted mainly to bile and then transferred to the intestinal tract, and finally excreted to feces. A portion of SN-38G excreted to the intestinal tract is deconjugated by β-glucuronidase of enteric bacteria, to thereby form active SN-38 again. The thus-formed SN-38 is metabolized and excreted via the steps of re-absorption by the mediation of a transporter present at the intestinal tract epithelium, enterohepatic circulation, glucuronidation by UGT in intestinal epithelial cells, and the like (Non-Patent Document 1). In the course of this metabolism, SN-38 damages the intestinal mucosa, to thereby possibly induce diarrhea. Also, some studies revealed that SN-38 adversely affects bone marrow, where active cell division occurs, to thereby induce erythrocytopenia, leukocytopenia, and thrombocytopenia.
One cause for adverse effects such as serious diarrhea and neutropenia was confirmed to be a change in exposure amount of SN-38 in the body caused by genetic polymorphism of UGT1A1. However, regarding therapeutic effects, there has been no report that the therapeutic effect can be predicted on the basis of pharmacokinetics, due to the complexity in vivo pharmacokinetics of CPT-11, which include conversion of CPT-11 (pro-drug) to SN-38 (active metabolite) and detoxication thereof; re-generation of SN-38 in the course of enterohepatic circulation; and metabolism of CPT-11 and formation of SN-38 from the metabolite thereof. Meanwhile, it has been reported that the carboxylesterase mRNA expression level in peripheral blood mononuclear cells correlates with the AUC ratio of SN-38 to SN-38G but does not correlate with the tumor regression effect (Non-Patent Document 2).
There have also been reported the following factors relating to the sensitivity or resistance to CPT-11: mutation of topoisomerase I, which is a target of SN-38, and expression level thereof; activity of carboxylesterase, the enzyme involved in conversion of CPT-11 to SN-38; ABC transporter genes (multidrug resistance protein (MRP)-1, MRP-2, and breast cancer resistant protein (BCRP)/ABCG2), which affects the intracellular accumulation amounts of CPT-11 and SN-38; and BCL2 family genes (Patent Document 1). Studies have been conducted on correlations of cell proliferation antigen Ki-67, tumor suppressor gene TP53, etc. with response to CPT-11 therapy. Recently, a clinical study has revealed that the plasma level of tissue inhibitor of metalloproteinase-1 (TIMP-1), the TIMP-1 having anti-apoptosis action, is significantly correlated with the clinical prognosis of a metastatic colorectal cancer patient having undergone CPT-11+5-FU combination therapy (Non-Patent Document 3). As described above, many studies have been carried out on CPT-11-sensitivity predicting biomarkers and sensitivity prediction methods, due to their necessity. However, a study has revealed that neither topoisomerase I (target) nor thymidylate synthase (possible 5-FU-sensitivity predicting factor) has clear correlation with therapeutic response in 5-FU+CPT-11 combination therapy (Non-Patent Document 4). Therefore, no biomarker or sensitivity prediction method which definitely predicts therapeutic response has been established.